EP0688768B1 - Verfahren zur Herstellung von 5H-Dibenz/b,f/azepin-5-carboxamid - Google Patents

Verfahren zur Herstellung von 5H-Dibenz/b,f/azepin-5-carboxamid Download PDF

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Publication number
EP0688768B1
EP0688768B1 EP94109605A EP94109605A EP0688768B1 EP 0688768 B1 EP0688768 B1 EP 0688768B1 EP 94109605 A EP94109605 A EP 94109605A EP 94109605 A EP94109605 A EP 94109605A EP 0688768 B1 EP0688768 B1 EP 0688768B1
Authority
EP
European Patent Office
Prior art keywords
acetic acid
water
iminostilbene
reaction
dibenz
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Expired - Lifetime
Application number
EP94109605A
Other languages
German (de)
English (en)
French (fr)
Other versions
EP0688768A1 (de
Inventor
Rudolf Dr. Eckardt
Hans-Joachim Dr. Jänsch
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Teva GmbH
Original Assignee
Arzneimittelwerk Dresden GmbH
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Priority to DE4307181A priority Critical patent/DE4307181C1/de
Application filed by Arzneimittelwerk Dresden GmbH filed Critical Arzneimittelwerk Dresden GmbH
Priority to AT94109605T priority patent/ATE170514T1/de
Priority to EP94109605A priority patent/EP0688768B1/de
Priority to ES94109605T priority patent/ES2123078T3/es
Publication of EP0688768A1 publication Critical patent/EP0688768A1/de
Application granted granted Critical
Publication of EP0688768B1 publication Critical patent/EP0688768B1/de
Anticipated expiration legal-status Critical
Expired - Lifetime legal-status Critical Current

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D223/00—Heterocyclic compounds containing seven-membered rings having one nitrogen atom as the only ring hetero atom
    • C07D223/14—Heterocyclic compounds containing seven-membered rings having one nitrogen atom as the only ring hetero atom condensed with carbocyclic rings or ring systems
    • C07D223/18—Dibenzazepines; Hydrogenated dibenzazepines
    • C07D223/22—Dibenz [b, f] azepines; Hydrogenated dibenz [b, f] azepines
    • C07D223/24—Dibenz [b, f] azepines; Hydrogenated dibenz [b, f] azepines with hydrocarbon radicals, substituted by nitrogen atoms, attached to the ring nitrogen atom
    • C07D223/26—Dibenz [b, f] azepines; Hydrogenated dibenz [b, f] azepines with hydrocarbon radicals, substituted by nitrogen atoms, attached to the ring nitrogen atom having a double bond between positions 10 and 11

Definitions

  • the invention relates to a method for producing 5H-dibenz / b, f / azepine-5-carboxamide.
  • This substance is under the free name carbamazepine introduced into the therapy. He has valuable physiological properties.
  • Carbamazepine is used to treat a wide range of Central nervous system disorders.
  • the present invention is based on the object a technically easy to use procedure for Manufacture of carbamazepine to find the above Does not have disadvantages.
  • the reaction of iminostilbene with an alkali metal cyanate can be carried out in the temperature range from 20 to about 100 ° C.
  • a preferred embodiment of the process according to the invention consists in gradually adding the alkali metal cyanate to a stirred suspension of iminostilbene in acetic acid mixtures at 60 ° C., the excess of cyanate being about 50 mol percent, based on iminostilbene.
  • the water content of the acetic acid / water mixture can be up to 20 percent by weight. If the reaction according to the invention takes place in an acetic acid / alcohol mixture, up to 10 percent by weight of alcohol can be present. Alcohols such as methanol and ethanol are preferably used in this reaction.
  • the alkali metal cyanate can be added gradually by adding the solid in portions. However, it is more advantageous to dropwise add an aqueous solution of the alkali metal cyanate, especially if the potassium cyanate which is readily soluble in water is used. Due to the possibility of dropping an aqueous solution of an alkali metal cyanate, the process according to the invention can be carried out in a technically particularly simple manner.
  • iminostilbene has a much lower basicity than the aforementioned aromatic primary amines and, on the other hand, iminostilbene has a much lower solubility in acetic acid than these amines. This low solubility drops further due to the addition of water and alcohol.
  • a stirred suspension of 100 g iminostilbene in 1000 ml of acetic acid is heated to 60 ° C. After that, inside of 160 minutes 54 g of 90% sodium cyanate in 11 Portions added. This is possible in the course of the reaction Iminostilben almost completely in solution before that Carbamazepine begins to crystallize. After finished Adding the sodium cyanate becomes the reaction mixture stirred at 60 ° C for a further 20 minutes.
  • a suspension of 100 g of iminostilbene in a mixture of 900 ml of anhydrous acetic acid and 100 ml of water is heated to 60 ° C. with stirring. 58.3 g of 90% sodium cyanate are then added in 16 portions over the course of 2.75 hours. After a reaction time of 2 hours, the mixture is briefly heated to 80 ° C. in order to dissolve small amounts of the undissolved iminostilbene. When the addition of sodium cyanate has ended, the reaction mixture is cooled to 18-20 ° C. and stirred at this temperature for 0.5 hours. The precipitated carbamazepine is filtered off, washed with 70 ml of a mixture of 63 ml of acetic acid and 9 ml of water and dried.
  • a suspension of 30 g iminostilbene in a mixture of 225 ml acetic acid and 45 ml water is heated to 60 ° C. with stirring. Then 17.5 g of 90% sodium cyanate are added in 16 portions within 2.75 hours. After a reaction time of 1.5 hours, the reaction mixture is briefly heated to 80 ° C. in order to dissolve small amounts of the undissolved iminostilbene. After the addition of the sodium cyanate has ended, the reaction mixture is kept at 60 ° C. for a further 10 minutes. The mixture is then cooled to 18-20 ° C. and stirred at this temperature for 1 hour. The precipitated carbamazepine is filtered off and washed with a 20 ml acetic acid-water mixture (6: 1) and dried.
  • a stirred suspension of 100 g iminostilbene in one Mixture of 1000 ml acetic acid and 150ml water is on Heated to 60 ° C. Thereafter, 60.8 g within 5 hours 98% potassium cyanate added in 13 portions.

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Other In-Based Heterocyclic Compounds (AREA)
  • Hydrogenated Pyridines (AREA)
EP94109605A 1993-03-08 1994-06-22 Verfahren zur Herstellung von 5H-Dibenz/b,f/azepin-5-carboxamid Expired - Lifetime EP0688768B1 (de)

Priority Applications (4)

Application Number Priority Date Filing Date Title
DE4307181A DE4307181C1 (de) 1993-03-08 1993-03-08 Verfahren zur Herstellung von 5H-Dibenz/b,f/azepin-5-carboxamid
AT94109605T ATE170514T1 (de) 1993-03-08 1994-06-22 Verfahren zur herstellung von 5h- dibenz/b,f/azepin-5-carboxamid
EP94109605A EP0688768B1 (de) 1993-03-08 1994-06-22 Verfahren zur Herstellung von 5H-Dibenz/b,f/azepin-5-carboxamid
ES94109605T ES2123078T3 (es) 1993-03-08 1994-06-22 Procedimiento para la preparacion de 5h-dibenz/b,f/azepin-5-carboxamida.

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
DE4307181A DE4307181C1 (de) 1993-03-08 1993-03-08 Verfahren zur Herstellung von 5H-Dibenz/b,f/azepin-5-carboxamid
EP94109605A EP0688768B1 (de) 1993-03-08 1994-06-22 Verfahren zur Herstellung von 5H-Dibenz/b,f/azepin-5-carboxamid

Publications (2)

Publication Number Publication Date
EP0688768A1 EP0688768A1 (de) 1995-12-27
EP0688768B1 true EP0688768B1 (de) 1998-09-02

Family

ID=25923720

Family Applications (1)

Application Number Title Priority Date Filing Date
EP94109605A Expired - Lifetime EP0688768B1 (de) 1993-03-08 1994-06-22 Verfahren zur Herstellung von 5H-Dibenz/b,f/azepin-5-carboxamid

Country Status (4)

Country Link
EP (1) EP0688768B1 (es)
AT (1) ATE170514T1 (es)
DE (1) DE4307181C1 (es)
ES (1) ES2123078T3 (es)

Families Citing this family (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
IT1272897B (it) * 1995-01-13 1997-07-01 I F C Iniziative Finanziaarie Processo per la produzione di 10-oxo-10,11-diidro-sh- -dibenz(b,f) azepin-5-carbossiammide
ES2209323T3 (es) * 1999-02-08 2004-06-16 Jubilant Organosys Limited Procedimiento de preparacion de 5-carbamoil-5h-dibenz(b,f)azepina.
WO2003106414A2 (en) 2002-06-14 2003-12-24 Taro Pharmaceuticals U.S.A., Inc. Method of preparing a 5h-dibenz[b,f]azepine-5-carboxamide
CA2452588C (en) 2003-12-08 2015-05-19 Shire Pharmaceutical Development Inc. Methods for the treatment of bipolar disorder using carbamazepine

Family Cites Families (11)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US2948718A (en) * 1960-08-09 New n-heterocyclic compounds
GB1087174A (en) * 1965-04-05 1967-10-11 Allen & Hanburys Ltd Piperidine derivatives
GB1246606A (en) * 1969-04-28 1971-09-15 Starogardzkie Zakl Farma Dibenzo-azepine derivatives
DD101670A1 (es) * 1972-02-22 1973-11-12
BG21940A1 (en) * 1975-08-20 1979-12-12 Georgiev Method of obtaining of derivatives of 5- (carbamoyl)- dibenz (b, f) azepine
NO154582C (no) * 1978-10-20 1986-11-05 Ferrosan Ab Analogifremgangsmaate for fremstilling av terapeutisk aktive difenyl-dibutylpiperazinkarboksamider.
JPS5681565A (en) * 1979-10-30 1981-07-03 Ciba Geigy Ag Manufacture of nnheterocyclic compound
US4847374A (en) * 1987-01-27 1989-07-11 Ciba-Geigy Corporation Process for the manufacture of N,N-(Dibenzohexatrienylene)ureas
DD298508A5 (de) * 1988-10-11 1992-02-27 Arzneimittelwerk Dresden Gmbh,De Verfahren zur herstellung von 5-carbamoyl-5h-dibenz/b,f/azepin
HU206321B (en) * 1989-10-16 1992-10-28 Alkaloida Vegyeszeti Gyar Improved process for producing 5-carbamoyl-5h-dibenz/b:f/azepine
DD297962A5 (de) * 1990-07-05 1992-01-30 �������@������������@��k�� Verfahren zur herstellung von 5-carbamoyl-5h-dibenz/b,f/azepin

Also Published As

Publication number Publication date
DE4307181C1 (de) 1994-11-10
ES2123078T3 (es) 1999-01-01
EP0688768A1 (de) 1995-12-27
ATE170514T1 (de) 1998-09-15

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